Project Summary/Abstract A paucity of functional [unreadable]-cells is a central feature of type 1 and type 2 diabetes and an urgent question in islet biology relates to plasticity of [unreadable]-cell mass in the long-term goal of developing strategies to treat both forms of the disease. This application is focused on the role of growth factors, especially insulin and IGF-I receptors and proteins in their signalling pathway, in regulation of [unreadable]-cell proliferation, apoptosis and secretory function. We use unique genetic mouse models lacking one or more proteins in the insulin/IGF-I signalling pathway in [unreadable]-cells and complement with studies in [unreadable] cell lines and primary islets derived from the knockouts for in vitro and ex vivo experiments. Based on Preliminry Data we seek to continue our studies with the following Specific Aims: Aim 1: Determine the role of insulin/IGF-I signaling in proinsulin processing and test the hypothesis that an intact insulin/IRS-2 pathway is essential for appropriate proinsulin processing. Aim 2: Define the alterations in endoplasmic reticulum (ER) stress in [unreadable] cells lacking proteins in the insulin signaling pathway and test the hypothesis that the insulin/IRS-2 pathway is essential to limit ER stress in [unreadable] cells: Our preliminary data indicates a direct role for the insulin receptor and IRS-2, but not IRS-1, in ER stress responses in [unreadable] cells. We plan to dissect the mechanisms and pathways that underlie enhanced ER stress in the context of insulin/IRS-2 signaling with a focus on IRE-1a and contrast the findings with the pathways mediated by IRS-1. Aim 3: Dissect the mechanisms that link the insulin/IGF-I signaling with proteins involved in the [unreadable]-cell growth response to insulin resistance: Our preliminary data using in vivo approaches builds on previous work and indicates critical roles for cyclin D2 and Px-1 in the compensatory islet growth response to insulin resistance. We will focus on these two proteins and explore their link with FoxO1 to dissect the mechanisms that underlie the proliferation responses especially in the context of differences between insulin and IGF-1 signaling. Aim 4: Define the islet and [unreadable]-cell proteome in mouse models of islet hyperplasia with a focus on identifying novel proteins involved in [unreadable]-cell proliferation and anti-apoptosis. Together we believe thee studies will provide novel insights into the role of growth factors in the regulation of [unreadable]-cell proliferation and apoptosis.